- Project summary: The infiltration of CD8+ T effector populations (CD8 effectors) into graft renal tubules has long been recognized as a key lesion in progression of clinical renal allograft rejection. Studies resulting from the previous funding period revealed a pivotal role for the integrin CD103 in promoting destruction of the graft renal tubules by donor-specific CD8 effector populations. Based on these data, we postulate that blockade of the CD103 pathway as an adjunct to conventional immunosuppressive strategies provides a means of promoting long-term survival of renal allografts. The overall objective of this proposal is to test this hypothesis. In order to achieve this goal, we will first elucidate the mechanisms by which CD103+CD8+ effectors destroy the graft renal tubules, and identify the origin of CD103+CD8+ effector populations that infiltrate renal allografts. The information gained from these studies will be used to develop optimal strategies for abrogating the contribution of CD103+CD8+ effector mechanisms to renal allograft destruction. The studies in Aim 1 will use gene expression analyses in combination with mouse renal transplant models to define the mechanisms by which CD103 expression promotes accumulation and subsequent destruction of the graft renal tubules by donor-specific CD8 effectors in the graft renal tubules. The studies in Aim 2 will use mouse renal allograft models to identify the precursors of CD103+CD8+ effectors that infiltrate epithelial allografts, and elucidate the role of local transforming growth factor-beta activity in their generation. The studies in Aim 3 will use rat kidney transplant models to determine the impact of CD103 blockade on development of tubular atrophy and interstitial fibrosis in vascularized renal allografts. Together, the proposed studies will elucidate the mechanisms by which CD8+ T cells destroy renal allografts and identify novel targets for therapeutic intervention in the important clinical problem of late graft loss. Relevance to public health: Current immunosuppressive strategies do not reliably prevent the occurrence of rejection episodes and long-term damage to the graft. Consequently, late graft loss now represents the major rejection problem in clinical renal transplantation. Thus, a better understanding of the pathways by which this occurs is likely to reveal novel targets for therapeutic intervention in this important clinical problem. [unreadable] [unreadable] [unreadable]